METABOLIC CONTROL OF T‐CELL DIFFERENTIATION
|Figure 7.17 Regulation Of T‐Cell Differentiation And Metabolism By Transcription Factors. T‐Cell Specific Metabolic Signatures Essential For Function, And Maintenance Of T‐Cell Subset, Are Driven By The Action Of Key Transcription Factors.|
It should now be clear that metabolic reprogramming plays a crucial role in T‐cell activation. However, the regulation does not end there. Specific metabolic programs are not only essential for the immune‐stimulatory function of particular T‐cell subsets, the individual nature of the metabolic signal also plays a crucial role in determining differentiation to the extent that inhibiting one metabolic signal over another is sufficient to shunt T‐cell differentiation towards a different outcome. Genetic studies have revealed an essential role for the mTOR pathway in promoting Th1, Th2, and Th17 differentiation, with stimulation of mTOR‐deficient cells leading mainly to differentiation of Tregs, which outlines a crucial role for mTOR in promoting effector T‐cell (Teff ) differentiation (Figure 7.17). Indeed, the layers of mTOR regulation extend to individual effector Th populations, with deletion of the mTORC1 activator Rheb biasing toward the Th2 effector cell phenotype while deletion of RICTOR, an essential component of the mTORC2 complex, favors generation of mainly Th1 and Th17 effectors (Figure 7.17). Thus, mTORC1 activation directs differentiation towards Th1 and Th17, while mTORC2 promotes Th2 production. While mTOR activation can skew towards Th1 or Th2 phenotypes, HIF1α has a particularly important role in the differentiation of Th17 cells by activating the Th17‐specific master transcription factor RORγt. In addition, HIF1α can also bind the Treg‐specific master regulator Foxp3, promoting its degradation and the inhibition of Treg differentiation. As such, genetic deletion of HIF1α blocks Th17 responses and skews differentiation to Treg cells.
The reliance of Teff cell differentiation on the mTOR pathway indicates that these cells depend heavily on glycolysis and this makes sense as Teffs must rapidly proliferate to combat infection. In contrast, Treg and memory T‐cells have a lower requirement for proliferation and as such, these cells rely mainly on fatty acid oxidation for energy, with minimal dependence on glycolysis. Indeed, Tregs display increased levels of AMPK, which represses mTOR activation and glycolysis. Whereas CD8+ T‐cells mimic CD4+ effectors for a reliance on aerobic glycolysis to fuel rapid proliferation, CD8+ memory T‐cells are long‐lived cells that patrol the lymphatic tissues looking for signs of a recurrence of infection. As such, these cells rely less on biosythesis and more on energy production and use fatty acid oxidation for their ATP generation requirements. This is reflected by increased expression of AMPK to repress glycolysis and CPT1a to drive lipid oxidation in mitochondria. Accordingly, deletion of TRAF6, which seems to be required for AMPK expression in memory CD8+ T‐cells, has been found to severely blunt the memory response after initial infection.